lactoferrin and Multiple-Sclerosis

Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs. Other researchers showed that EPO can act as a protectant against severe brain injury and status epilepticus in rats. Therefore, we tried rhLF as a protector against the severe neurologic disorders developed in rats, such as the rotenone-induced model of Parkinson's disease and experimental autoimmune encephalomyelitis as a model of multiple sclerosis, and observed its capacity to mitigate the grave symptoms. Moreover, an intraperitoneal injection of rhLF into mice 1 h after occlusion of the medial cerebral artery significantly diminished the necrosis area measured on the third day in the ischaemic brain. During this period EPO was synthesized in various murine tissues. It was known that EPO induces nuclear translocation of Nrf2, which, like HIF-1-alpha, is a transcription factor. In view that under conditions of hypoxia both factors demonstrate a synergistic protective effect, we suggested that LF activates the Keap1/Nrf2 signaling pathway, an important link in proliferation and differentiation of normal and malignant cells. J774 macrophages were cultured for 3 days without or in the presence of ferric and ferrous ions (RPMI-1640 and DMEM/F12, respectively). Then cells were incubated with rhLF or Deferiprone. Confocal microscopy revealed nuclear translocation of Nrf2 (the key event in Keap1/Nrf2 signaling) induced by apo-rhLF (iron-free, RPMI-1640). The reference compound Deferiprone (iron chelator) had the similar effect. Upon iron binding (in DMEM/F12) rhLF did not activate the Keap1/Nrf2 pathway. Added to J774, apo-rhLF enhanced transcription of Nrf2-dependent genes coding for glutathione S-transferase P and heme oxygenase-1. Western blotting revealed presence of Nrf2 in mice brain after 6 days of oral administration of apo-rhLF, but not Fe-rhLF or equivalent amount of PBS. Hence, apo-LF, but not holo-LF, induces the translocation of Nrf2 from cytoplasm to the nucle

Topics: Animals; Brain Ischemia; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Humans; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; Rats; Rats, Wistar; Recombinant Proteins

Free radicals are molecules that contain at least one unpaired electron and by nature are highly reactive and potentially destructive. Free radical damage can play an important role of demyelination. Glutathione peroxidase, which plays a role in free radical defenses, and myeloperoxidase and lactoferrin, which are considered to reflect the strength of oxidative stress, were examined by monoclonal antibody-based enzyme immunoassay on serum samples taken from patients with neuroimmunological disorders, namely, 35 multiple sclerosis(MS), and 2 Baló disease, 10 Guillain-Barré syndrome(GBS), and 25 human T-lymphotropic virus type-1 associated myelopathy (HAM). The levels of glutathione peroxidase in active phase of MS (8.37 +/- 5.59 micrograms/ml: p < 0.05) were increased rather than in inactive phase (5.05 +/- 2.44 micrograms/ml) and control (5.41 +/- 1.40 micrograms/ml), the levels of myeloperoxidase in HAM (95.5 +/- 89.1 ng/ml: p < 0.05) were increased rather than in controls (21.5 +/- 4.1 ng/ml), and the levels of lactoferrin were not significantly increased than in other disease and control. Moreover the levels of myeloperoxidase and lactoferrin are increased in Baló disease (myeloperoxidase 487, 762 ng/ml; not significant, lactoferrin 2.58, 2.77 ng/ml; not significant) than in control (myeloperoxidase 21.5 +/- 4.1 ng/ml, lactoferrin 0.69 +/- 0.32 ng/ml). In conclusion, we have here first demonstrated that the levels of these enzyme were not paralleled in MS and Baló diseases. In GBS the levels of all these enzyme were not increased. Thus, these findings suggest that these enzyme may play an important role of the disease activity of Baló, and may reflect the activity of the defense of MS.

Topics: Adult; Diffuse Cerebral Sclerosis of Schilder; Free Radicals; Glutathione Peroxidase; Guillain-Barre Syndrome; Humans; Lactoferrin; Middle Aged; Multiple Sclerosis; Oxidative Stress; Paraparesis, Tropical Spastic; Peroxidase

This study sought to identify abnormalities in the levels of iron transport proteins in patients with superficial siderosis of the central nervous system. We compared patients with superficial siderosis (n = 7) with patients suffering from various other neurological disorders (n = 176, total). CSF and serum levels of lactoferrin, and CSF levels of transferrin were measured by enzyme-linked immunosorbent assay. Serum transferrin was measured by nephelometry. Lactoferrin, but not transferrin, levels in the CSF were significantly elevated in superficial siderosis. Unexpectedly, CSF transferrin was decreased in multiple sclerosis patients. Enhanced CSF lactoferrin may reflect an increased iron transport requirement in the central nervous system in superficial siderosis and might be a useful measure for monitoring response to therapy.

Topics: Central Nervous System Diseases; Humans; Lactoferrin; Meningitis, Bacterial; Multiple Sclerosis; Nervous System Diseases; Siderosis; Transferrin

Topics: Autoantibodies; Autoimmunity; Humans; Lactoferrin; Multiple Sclerosis

ECP (eosinophil cationic protein) has been measured by means of a specific radioimmunoassay in the cerebrospinal fluid (CSF) from 210 individuals with various diseases affecting the central nervous system. In the same specimens lactoferrin and albumin were measured as well, as indicators of neutrophil-involved inflammation and damage to the blood-brain barrier. From a patient reference group (n = 39) the upper "normal" limit for ECP was estimated to 1.7 microgram/l. In patients with acute cerebrovascular disease (n = 108) ECP levels were elevated in 38% of the cases which was a significantly (P less than 0.001) greater proportion than seen for lactoferrin (7%). In patients with acute infections of the CNS (n = 30) 67% had raised ECP levels with significantly higher levels (P less than 0.001) in those having bacterial infections. The ECP levels were significantly correlated (P less than 0.001) to the lactoferrin-levels in the whole infectious group. In patients with tumours (n = 25) raised levels of ECP were found in 67% of those with malignant and in 6% of those having benign tumours. This difference was statistically significant (P = 0.001). The ECP levels were closely related to those of lactoferrin (P less than 0.001) and albumin (P less than 0.005). Of the patients with multiple sclerosis (n = 19) 25% had raised ECP levels. This proportion was not significantly different from those having raised lactoferrin levels. In three patients extremely high ECP levels (70-455 micrograms/l) were found and a causal relationship between ECP and the brain tissue damage in these patients is suggested. In comparison with the neutrophil-related data the findings suggest a preferential involvement of eosinophils in some diseases affecting the central nervous system.

Topics: Adolescent; Adult; Aged; Blood Proteins; Brain Neoplasms; Central Nervous System Diseases; Cerebrovascular Disorders; Eosinophil Granule Proteins; Female; Humans; Lactoferrin; Male; Meningitis; Middle Aged; Multiple Sclerosis; Ribonucleases; Serum Albumin